Identification of therapeutic agents effective in the treatment of neoplastic diseases or for the treatment of neurological disorders is the subject of significant research efforts.
Protein kinases represent a large family of proteins which play a central role in the regulation of a wide variety of cellular processes and maintaining control over cellular function. A partial list of such kinases includes abl, Akt, bcr-ab1, Blk, Brk, Btk, c-kit, c-met, c-src, CDK1, CDK2, CDK3, CDK4, CDK5, CDK6, CDK7, CDK8, CDK9, CDK10, cRaf1, CSF1R, CSK, EGFR, ErbB2, ErbB3, ErbB4, Erk, Fak, fes, FGFR1, FGFR2, FGFR3, FGFR4, FGFR5, Fgr, FLK-4, flt-1, Fps, Frk, Fyn, Hck, IGF-1R, INS-R, Jak, KDR, Lck, Lyn, MEK, p38, PDGFR, PIK, PKC, PYK2, ros, tie, tie2, TRK, Yes, and Zap70. As such, inhibition of kinases has become an important therapeutic target.
Cell proliferation is the rapid reproduction of cells, such as by cell division. The cell cycle, which controls cell proliferation, is itself controlled by a family of serine-threonine kinases called cyclin dependent kinases (CDKs). The regulation of CDK activation is complex, and requires the association of the CDK with a member of the cyclin family of regulatory subunits. A further level of regulation occurs through both activating and inactivating phosphorylations of the CDK subunit. The coordinate activation and inactivation of different cyclin/CDK complexes is necessary for normal progression through the cell cycle. Both the critical G1-S and G2-M transitions are controlled by the activation of different cyclin/CDK activities. Loss of control of CDK regulation is a frequent event in hyperproliferative diseases and cancer. (T. Noguchi et al., Am. J. Pathol., 156, 2135–47 (2000)) As such, inhibition of CDKs has become an important target in the study of chemotherapeutics (A. Senderowicz and E. Sausville, J. Nat. Canc. Instit., 92, 376–87 (2000))
Kinases have also been implicated in diseases and disorders of the central nervous system. For example, patients suffering from stroke, Alzheimer's disease or Parkinson's disease would benefit from the inhibition of kinases. Cdk5 has been shown to be involved in Alzheimer's pathology (R. Maccioni, et al., Eur. J. Biochem., 268, 1518–27 (2001)) and with neuronal development (G. Paglini and A. Caceres, Fur. J. Biochem., 268, 1528–33 (2001)).
Protein kinases also control programmed cell death, also known as apoptosis. Apoptosis is a ubiquitous physiological process used to eliminate damaged or unwanted cells in multicellular organisms. Disregulation of apoptosis is believed to be involved in the pathogenesis of many human diseases. The failure of apoptotic cell death has been implicated in various cancers, as well as autoimmune disorders. Conversely, increased apoptosis is associated with a variety of diseases involving cell loss such as neurodegenerative disorders and AIDS. As such, inhibition of apoptosis has become an important therapeutic target. Cdk5 has been shown to be involved in apoptosis pathology (A. Catania et al., Neuro-Oncology, 89–98 (April 2001)).
Substituted heterocyclic compounds are known in the pesticide art. WO00/24735, published May 4, 2000, describes 1-pyridyl-1,2,4-triazoles as pesticides. WO00/24739, published May 4, 2000, describes substituted 1,2,4-triazoles as pesticides. WO97/01552, published Jan. 16, 1997, describes substituted 1,2,4-triazoles as antifungal agents. DE4204492 describes substituted benzamides as pesticides. WO98/57969, published Dec. 23, 1998, describes heterocyclylpyridines as pesticides. GB2293380, published Mar. 27, 1996, describes the use of heterocyclic compounds as pesticides. U.S. Pat. No. 5,693,667, issued Dec. 2, 1997, describes heterocyclic compounds for the treatment of take-all disease. EP468695 describes fungicide compounds. U.S. Pat. No. 5,294,596, issued Mar. 15, 1994, describes herbicidal triazolinones. U.S. Pat. No. 5,395,818, issued Mar. 7, 1995, describes herbicidal triazolinones.
Substituted thiazoles also are known in the pesticide art. U.S. Pat. No. 4,260,765, issued Apr. 7, 1981, describes 2-(3-pyridyl)-5-thiazolecarboxamides for the treatment of aphids. U.S. Pat. No. 5,945,380, issued Aug. 31, 1999, describes 4-(4-pyridyl)pyrazoles as insecticides. WO89/00568, published Jan. 26, 1989, describes nicotine derivatives as fungicides.
Heterocyclic ureas are known in the pharmaceutical art. WO99/23091, published May 14, 1999, describes heterocyclic compounds as anti-inflammatories. WO99/32455, published Jul. 1, 1999, describes heterocyclic ureas as RAF kinase inhibitors. WO99/32110, published Jul. 1, 1999, describes heterocyclic ureas as p38 kinase inhibitors. WO99/32106, published Jul. 1, 1999, describes heterocyclic ureas as RAF kinase inhibitors. WO99/32111, published Jul. 1, 1999, describes heterocyclic ureas as p38 kinase inhibitors. WO99/32436, published Jul. 1, 1999, describes urea compounds as inhibitors of RAF kinase. WO99/32463, published Jul. 1, 1999, describes urea compounds that inhibit p38 kinase. WO98/52558, published Nov. 26, 1998, describes urea compounds for the inhibition of p38 kinase. WO99/00357, published Jan. 7, 1999, describes the use of urea compounds as inhibitors of p38 kinase. WO99/58502, published Nov. 18, 1999, describes urea compounds as inhibitors of p38 kinase. U.S. Pat. No. 5,821,245, issued Oct. 13, 1998, describes substituted naphthalene derivatives for treating cell growth. GB patent 1,437,895 describes 2-thiazolyl ureas for the treatment of ulcers. U.S. Pat. No. 5,364,871, issued Nov. 15, 1994 describes thiazoles as anti-ulcer compounds. WO99/21555, published May 6, 1999, describes pyridyl-substituted thiazoles as adenosine A3 receptor antagonists. WO96/23783 describes indole derivatives as 5-HT receptor antagonists. U.S. Pat. No. 5,208,248 describes indazole derivatives as 5-HT receptor antagonists. WO99/46244, published Sep. 16, 1999 describes heterocyclic compounds as tyrosine phosphatases. GB patent 2,263,109, published Jul. 14, 1993, describes pyridylthiazoles as PAF-receptor antagonists.
Thiazole compounds have also been described as inhibitors of CDK. WO00/26203, published May 11, 2000, describes 2-ureidothiazoles as inhibitors of cdk. WO99/65884 describes 2-aminothiazoles as inhibitors of CDK. WO99/24416 describes 2-aminothiazoles as inhibitors of CDK.
However, compounds of the current invention have not been described as inhibitors of cell proliferation or apoptosis such as for the treatment of cancer or stroke.